1. Field of the Invention
The present invention relates to broad-spectrum antiviral compounds targeting the 3C or 3C-like (“3CL”) proteases of the picornavirus-like supercluster.
2. Description of Related Art
Many viruses encode polyproteins with proteases which catalyze their subsequent cleavage to the mature functional proteins and are essential for viral replication. Previous attempts have been made to inhibit viral activity by targeting such proteases. However, most protease inhibitors have a short range of specificity that is genus-, species-, or even strain-specific due to structural variations in the viral proteases. Thus, broad spectrum antivirals are rare and have proven elusive to researchers.
Caliciviruses, such as the norovirus and sapovirus genera, cause acute gastroenteritis in humans and animals. Noroviruses are the most common cause of acute viral gastroenteritis in the United States and worldwide, accounting for ˜21 million cases of gastroenteritis in the U.S. alone. Noroviruses are highly contagious and cause outbreaks in enclosed settings such as navy and cruise ships, army barracks, schools, and hospitals. Noroviruses are very stable in the environment and refractory to many common disinfectants, with only a few virions required to initiate virus infection and shedding which could be a source for further contamination. Norovirus infection constitutes an important public health problem, as well as a potential bioterrorism threat, and is classified as a Category B priority pathogen by NIAID and a class B bioterrorism agent by the CDC. The problem is further compounded by the absence of specific norovirus antiviral therapeutics or vaccines. Vaccine development for human noroviruses faces additional obstacles because norovirus strain diversity is high, and immunity to one strain does not necessarily provide protection from infection with other strains. Furthermore, repeat infections with the same norovirus strain in adults indicate that long-term immunity may be absent. Thus, there is currently an urgent and unmet need for the development of antiviral therapeutics for the treatment and prevention of norovirus infection. There is also a need for antiviral therapies for treating and preventing other viruses, such as medically important coronaviruses and picornaviruses, including but not limited to severe acute respiratory syndrome coronavirus (SARS-CoV), feline infectious peritonitis virus (FIPV), human rhinovirus (HRV), coxsackievirus (CV), and enteroviruses (EV).